Leukotriene B4 (LTB4) is a potent pro-inflammatory activator of inflammatory cells, including neutrophils, monocytes, macrophages, T cells and B cells. Immune cell priming and activation by LTB4 can promote chemotaxis, adhesion, free radical release, degranulation and cytokine release. LTB4 plays a significant role in the amplification of many inflammatory disease states including asthma, inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), arthritis, psoriasis, and atherosclerosis.
LTB4 levels are elevated in brochoalveolar lavage fluid from patients with scleroderma lung disease. Therefore, a therapeutic agent that inhibits the biosynthesis of LTB4 or the response of cells to LTB4 may be useful for the treatment of these inflammatory conditions.
The biosynthesis of LTB4 from arachidonic acid (AA) involves the action of three enzymes: phospholipase A2 (PLA2), to release AA from the membrane lipids; 5-lipoxygenase (5-LO), to form the unstable epoxide Leukotriene A4 (LTA4); and leukotriene A4 hydrolase (LTA4-h), to form LTB4.
LTA4-h is a monomeric, soluble 69 kD bifunctional zinc-dependent metalloenzyme of the M1 class of metallohydrolases. It catalyzes two reactions: the stereospecific epoxide hydrolase reaction to convert LTA4 to LTB4 and a peptidase cleavage of chromogenic substrates. A reduction of LTB4 production by an inhibitor of LTA4-h activity has therapeutic potential in a wide range of diseases. LTA4-h inhibitors have been shown to be effective anti-inflammatory agents in preclinical studies, thus providing the ability to prevent and/or treat leukotriene-mediated conditions, such as inflammation. LTA4-h inhibitors are disclosed, for example, in U.S. Pat. No. 7,737,145 and U.S. Patent Application Publication No. 2010/0210630A1, the contents of each of which are incorporated by reference herein.
It would be advantageous to develop additional LTA4-h inhibitors.